Tobacco dependence is a serious public health problem. An understanding of why cigarette use is so hard to quit may come from an understanding of the mechanisms of action of nicotine. Nicotine is the primary psychoactive substance in cigarettes, believed to mediate their addictive properties through the rate of clearance of nicotine from the body. Fast metabolizers smoke more and find it harder to stop smoking than slow metabolizers. Despite the characterization of the behavioral differences between fast metabolizers and slow metabolizers, differences between the two in brain systems that underlie smoking have not been delineated. Dopamine is the final common path of all addictive substances and activation of the dopamine system is thought to underlie the addictive potential of nicotine. In our laboratories, we use Positron Emission Tomography (PET) imaging to measure dopamine transmission in the human brain. At the Centre for Addiction and Mental Health, we have developed a method to study the impact of tobacco smoking on dopamine transmission in the human brain. With the use of the radiotracer [11C]-(+)-PHNO, we have the most sensitive method in the world to study changes in dopamine levels in response to smoking. The purpose of the present proposal will be to provide the first direct evaluation of the impact of different rates of nicotine metabolism on dopamine transmission. To this end, we will image the dopamine system either at baseline or after smoking. Comparisons will be made between fast metabolizers and slow metabolizers. It is hypothesized that, in keeping with our preliminary data, slow metabolizers will exhibit greater increases in dopamine levels following smoking. Non-treatment seeking participants will visit our PET centre for two PET scans that will be separated by one week. During one scan, the participant will be abstinent from smoking and just prior to the other, the participants will smoke a cigarette. Participants will then underg PET scans. Subjective measures of pleasure and craving will also be taken, as will smoking topography, to assess the effect of rate of metabolism of perception of cigarettes.